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Inactivation of the Pseudomonas-Derived Cephalosporinase-3 (PDC-3) by Relebactam

Melissa D Barnes1,2, Christopher R Bethel1, Jim Alsop3

  • 1Research Service, Louis Stokes Cleveland Department of Veterans Affairs, Cleveland, Ohio, USA.

Antimicrobial Agents and Chemotherapy
|March 14, 2018
PubMed

Insights

Relebactam effectively inhibits Pseudomonas-derived cephalosporinase (PDC), a key enzyme in multidrug-resistant Pseudomonas aeruginosa. This combination therapy restores imipenem susceptibility in a significant majority of resistant bacterial isolates.

Area of Science:

  • Microbiology
  • Infectious Diseases
  • Pharmacology

Background:

  • Pseudomonas aeruginosa is a major Gram-negative pathogen causing severe infections.
  • Pseudomonas-derived cephalosporinase (PDC) is a critical inducible beta-lactamase conferring resistance to cephalosporins in P. aeruginosa.

Purpose of the Study:

  • To evaluate the inhibitory activity of relebactam against PDC-3.
  • To assess the efficacy of relebactam in restoring imipenem susceptibility in multidrug-resistant P. aeruginosa.

Main Methods:

  • Enzymatic assays were performed to determine the inhibition kinetics of relebactam against PDC-3 (k2/K and koff values).
  • Susceptibility testing was conducted on clinical isolates of multidrug-resistant P. aeruginosa using imipenem alone and in combination with relebactam or cilastatin.

Main Results:

  • Relebactam demonstrated potent inactivation of PDC-3, with kinetic parameters k2/K = 41,400 M-1 s-1 and koff = 0.00095 s-1.
  • Relebactam resensitized 62% of multidrug-resistant P. aeruginosa isolates to imipenem.
  • Imipenem-cilastatin alone only restored susceptibility in 21% of the isolates.

Conclusions:

  • Relebactam is a potent inhibitor of PDC-3, a key beta-lactamase in P. aeruginosa.
  • The combination of relebactam with imipenem-cilastatin significantly enhances treatment efficacy against multidrug-resistant P. aeruginosa infections.
Keywords:
AmpCPDC-3Pseudomonas aeruginosadiazabicyclooctane inhibitorimipenemrelebactamβ-lactamβ-lactamase

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